The aim of this proposal is to evaluate the ability of recombinant attenuated Salmonella that express genes of Herpes simplex virus (HSV) to induce protective immunity against viral challenge in animal model systems. The vector system, although administered via the oral route, is expected to induce protective levels of antibody and perhaps cell mediated immunity at mucosal sites distant from the site of immunization and, in addition, should induce protective levels of systemic immunity. Effective immunity at mucosal sites may serve to prevent infection, an important objective for antiherpesvirus vaccines since infection is invariably followed by latency and the likelihood of recrudescent disease. To test the effectiveness of mucosal immunity, mice will be challenged via the respiratory and vaginal routes. Systemic immunity will be evaluated by control of subsequent zosteriform spread of virus following infection via the dermis. Various Salmonella vectors expressing HSV genes in different ways will be evaluated as vaccines and measurements will be made of the extent of the humoral and T cell mediated immune responses at mucosal sites, serum and lymphoid tissues. Evidence will be sought for correlations between in vitro parameters of immunity and the subsequent response to viral challenge in the different models. Especial emphasis will be directed at the cytotoxic T lymphocyte responses since it is hypothesized that for solid immunity to HSV this form of immunity must be included in the immune response. Our research will evaluate if a recombinant attenuated Salmonella vector system holds promise as a means of vaccinating against HSV in man.